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By Malorye A. Branca

August 18, 2004 | The gene underlying a rare, fatal inherited disorder, which may shed light on the mystery of sudden infant death syndrome (SIDS), has been identified thanks to new technology and old-fashioned medicine.

Doctors in a small Pennsylvania Amish community and researchers at the Translational Genomics Research Institute (TGen) in Arizona were able to pinpoint the gene in record time, with only a handful of samples, using Affymetrix’s GeneChip Mapping 10K arrays and Silicon Genetics’ Varia genotyping software.

“This is not the ‘gene for SIDS,’” cautions Debra Weese-Mayer of Rush University in Chicago. However, the discovery supports the notion that genetics plays a role in at least some SIDS cases. The work was published online by the Proceedings of the National Academy of Sciences.

This rare inherited disorder is named “sudden infant death with dysgenesis of testes” (or SIDDT) because boys with the condition have abnormal testes. The affected children invariably die of sudden cardiac and respiratory arrest within the first year of life.

In nine related Amish families, the disease is clearly inherited as a recessive disorder: In two generations, 21 children died. “One feature that distinguishes these babies is an unusual cry,” says Erik G. Puffenberger, laboratory director at the Clinic for Special Children and first author of the PNAS paper. The cry is described as similar to the staccato bleating of a goat. “But there is no way to identify these babies at birth, even though they are neurologically abnormal,” Puffenberger says.

Starting with DNA samples from four affected children, their parents, and relatives, the researchers narrowed the defective gene to a stretch of chromosome 6. Two of the 27 genes in the critical region were expressed in the testis, one of which, TSPYL, proved to be the errant gene. All the deceased infants possessed two copies of the mutated gene, while each of their parents carried one faulty copy.

The study would have taken much longer, and many more samples, without powerful new technology. “With these [Affymetrix] chips, we can analyze more than 10,000 SNPs at once. That’s about one every 210,000 base pairs,” says Dietrich Stephan, senior author and TGen’s director of neurogenomics. Stephan’s TGen laboratory is set up for “industrialized” genotyping, completing analysis of the first dozen samples in only three weeks, rather than the months frequently required to process hundreds of samples.

TGen chose the Affymetrix platform because of the group’s familiarity with that company’s expression analysis chips and because of the chips’ “unprecedented throughput, accuracy, and minimal cost,” Stephan says. Affymetrix donated the chips for this particular study.

Stephan also credits the role of the Varia program. “Most of the traditional linkage analysis packages are not geared up to handle these many genotype calls, so the genomewide analysis must be chopped up into smaller-sized pieces and then stitched together afterwards,” he says. “The visualization capabilities of the Varia software are excellent.”

“This is a very important piece of the SIDS puzzle,” Weese-Mayer says. Understanding SIDS is complicated: Mysterious sudden death in infants can be due to inborn metabolic disorders, as well as parental psychiatric disorders. Michael Patton, a pediatrician at St. George’s Hospital Medical School in London, cautions that it can be difficult to “extrapolate” studies on isolated communities such as the Amish to groups of more mixed descent.

Nevertheless, the study clearly opens up promising new avenues for SIDS research. As Puffenberger says, “This [gene] may not cause most SIDS, but perhaps this gene is working in concert with other genes, and by following this trail we will learn even more.”

Further Reading:
Puffenberger, E.G. et al. "Mapping of sudden infant death and dysgenesis of the testes syndrome (SIDDT) by a high-density SNP genome scan and identification of TSPYL loss of function." PNAS Online Early Edition, July 19, 2004.


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